In humans, early B-lymphoid derived neoplasms such as the cu+ cells in t(1:19) pre-B cell acute lymphoblastic leukemia often have an immunoglobulin (Ig) rearrangement status consistent with an arrest in maturation at a specific point in lymphoid differentiation. However, these cells can co-express markers characteristic of different developmental stages. Thus, these malignant clones may represent the product of an aberrant differentiation process or the outgrowth of rare or transient B-lymphoid progenitors inherently susceptible to transformation during B cell development. The ordered rearrangements of immunoglobulin component genes promote differentiation and serve as molecular "markers" of specific stages during B-cell ontogeny. Recombinase Activating Gene (RAG) deficient and JH deficient mice alone or bearing Ig transgenes are unique murine models harboring genetically and functionally defined, developmentally arrested pro-B cell (all Ig genes germline), pre-B cell (heavy chain Ig genes rearranged, light chain genes germline), or immature B cell (heavy and light chain genes rearranged) lymphoid populations. Embryonic stem (ES) cells harboring these defined mutations will be complemented with informative combinations of Ig transgenes, transgene components, and leukemogenic fusion protein expression constructs, then differentiated in RAG-/- chimeras using an assay known as the RAG-/-blastocyst complementation system. Initial studies will use expression constructs encoding for the p190 bcr-abl product, and the E2A-PBX1 fusion protein. These experiments will elucidate whether the phenotypic and functional differences distinguishing specific precursor B-lineage populations predispose or protect against leukemogenesis, and contribute to the goal of developing exquisitely narrow diagnostic and therapeutic strategies in the diagnosis and treatment of acute lymphoblastic leukemia.